Cardiovascular Disease Risk is not about high cholesterol!

What causes dysfunction and chronic inflammation?

In functional medicine, chronic inflammation is recognized as a key factor in the development of endothelial dysfunction and increased risk for cardiovascular disease (CVD). This approach emphasizes a holistic understanding of how various physiological processes and lifestyle factors contribute to health and disease. Here’s a detailed explanation of the relationship between chronic inflammation, endothelial dysfunction, and CVD risk from a functional medicine perspective:

Chronic Inflammation and Endothelial Dysfunction

**1. Mechanisms of Chronic Inflammation:

• Immune Response: Persistent activation of the immune system due to infections, autoimmune disorders, or other chronic conditions leads to continuous release of pro-inflammatory cytokines (e.g., TNF-α, IL-6).
• Oxidative Stress: Chronic inflammation is often accompanied by oxidative stress, where excess reactive oxygen species (ROS) damage cellular components, including the endothelium.
• Metabolic Dysregulation: Conditions such as insulin resistance, obesity, and dyslipidemia contribute to chronic inflammation through increased levels of circulating free fatty acids and adipokines.

**2. Impact on Endothelium:

• Cellular Damage: Inflammatory mediators and oxidative stress directly damage endothelial cells, impairing their function.

• Impaired Nitric Oxide Production: Inflammation reduces the availability of nitric oxide (NO), a crucial molecule for vascular health, leading to vasoconstriction and reduced blood flow.

• Increased Permeability: Chronic inflammation increases endothelial permeability, allowing more lipids and immune cells to infiltrate the arterial wall, promoting atherosclerosis.

Increased Risk for Cardiovascular Disease

**1. Atherosclerosis Development:

• Lipid Accumulation: Damaged endothelium facilitates the deposition of LDL cholesterol in the arterial wall, where it becomes oxidized (oxLDL).
• Foam Cell Formation: Macrophages ingest oxLDL, transforming into foam cells that accumulate to form fatty streaks, the precursors to atherosclerotic plaques.
• Plaque Progression: Chronic inflammation promotes the growth and instability of these plaques, increasing the risk of rupture and thrombosis.

**2. Cardiovascular Events:

• Plaque Rupture: Inflammatory processes weaken the fibrous cap of atherosclerotic plaques, making them more likely to rupture and cause acute cardiovascular events like myocardial infarction (heart attack) and stroke.
• Thrombosis: Endothelial dysfunction and inflammation enhance the pro-thrombotic environment, increasing the likelihood of clot formation.

Functional Medicine Approach

**1. Identifying Root Causes:

• Comprehensive Assessment: Functional medicine practitioners conduct thorough assessments to identify underlying causes of chronic inflammation, such as infections, dysbiosis (gut microbiota imbalance), food sensitivities, and environmental toxins.
• Personalized Treatment Plans: Interventions are tailored to the individual’s unique physiological and lifestyle factors, addressing the root causes of inflammation.

**2. Interventions:

• Anti-inflammatory Diet: Emphasis on whole, unprocessed foods rich in anti-inflammatory nutrients (e.g., omega-3 fatty acids, antioxidants).
• Gut Health Optimization: Strategies to improve gut microbiota balance, such as probiotics, prebiotics, and addressing dysbiosis.
• Lifestyle Modifications: Incorporating regular physical activity, stress management techniques, and adequate sleep to reduce systemic inflammation.
• Nutraceuticals and Supplements: Use of targeted supplements (e.g., curcumin, quercetin, omega-3s) to reduce inflammation and support endothelial function.

**3. Monitoring and Adjustment:

Chronic Inflammation

 

• Biomarker Tracking: Regular monitoring of inflammatory and cardiovascular biomarkers (e.g., hsCRP, oxLDL, ADMA/SDMA, homocysteine, lipid profile) to assess the effectiveness of interventions and adjust treatment plans as needed.
• Continuous Optimization: Functional medicine involves ongoing assessment and optimization, ensuring that interventions remain aligned with the patient’s evolving health status.

In functional medicine, the interplay between chronic inflammation, endothelial dysfunction, and cardiovascular risk is addressed through a comprehensive, personalized approach. By identifying and addressing the root causes of inflammation and implementing holistic interventions, functional medicine aims to improve endothelial health and reduce the risk of cardiovascular disease, emphasizing the importance of systemic balance and optimal functioning of all body systems.

Mechanisms of Chronic Inflammation and Endothelial Dysfunction

1. Hypertension:

• Shear Stress: Chronic high blood pressure creates shear stress on the endothelial cells lining blood vessels. This stress leads to endothelial dysfunction by causing mechanical injury, increased permeability, and promoting inflammatory responses.

2. Toxins:

• Cellular Stress: Environmental toxins (e.g., smoking, pollution, heavy metals) induce oxidative stress and inflammation in endothelial cells. This stress disrupts normal cellular functions and promotes endothelial dysfunction.

3. Insulin Resistance:

• Insulin resistance leads to hyperglycemia and hyperinsulinemia, which cause endothelial cells to produce more reactive oxygen species (ROS). This oxidative stress contributes to inflammation and endothelial dysfunction.

4. Elevated Cholesterol:

• LDL and oxLDL: Elevated LDL cholesterol, especially when oxidized (oxLDL), is taken up by endothelial cells and macrophages, leading to foam cell formation and atherogenesis. This process is inflammatory and contributes to endothelial dysfunction.

5. Chronic Inflammation:

• Chronic systemic inflammation, driven by factors such as autoimmune diseases, chronic infections, and lifestyle factors, perpetuates a state of endothelial dysfunction by maintaining a pro-inflammatory environment.

6. Trimethylamine N-oxide (TMAO):

• TMAO, a metabolite produced by gut bacteria from dietary choline and carnitine, has been implicated in promoting inflammation, endothelial dysfunction, and atherosclerosis.

Factors Contributing to Chronic Inflammation

1. Gut Dysbiosis:

• Imbalances in gut microbiota can lead to increased intestinal permeability (“leaky gut”), allowing bacterial endotoxins (e.g., lipopolysaccharides) to enter the bloodstream and trigger systemic inflammation.

2. Periodontal Disease:

• Chronic infections in the gums lead to persistent local and systemic inflammatory responses, contributing to endothelial dysfunction and cardiovascular disease.

3. Diabetes:

• Chronic hyperglycemia induces oxidative stress, inflammation, and advanced glycation end-product (AGE) formation, which damage endothelial cells and impair their function.

4. Autoimmune Diseases:

• Autoimmune conditions (e.g., rheumatoid arthritis, lupus) involve chronic inflammation and immune-mediated damage to endothelial cells, exacerbating endothelial dysfunction.

5. Chronic Infections:

• Persistent infections (e.g., HIV, hepatitis) maintain a state of chronic inflammation, which negatively affects endothelial health.

Factors Influencing Cholesterol Levels

1. Excess Production:

• Genetic factors and dietary influences can lead to overproduction of cholesterol by the liver, contributing to elevated blood cholesterol levels.

2. Excessive Gut Reabsorption:

• The enterohepatic circulation involves the reabsorption of bile acids and cholesterol from the intestine. Excessive reabsorption can increase cholesterol levels in the blood.

3. Poor Serum Uptake by the Liver:

• Defects in LDL receptor function or expression reduce the liver’s ability to clear LDL from the bloodstream, leading to elevated LDL levels.

4. Dietary Cholesterol:

• Although dietary cholesterol contributes a small portion to blood cholesterol levels, the liver adjusts its own cholesterol production based on dietary intake, making endogenous production a more significant factor.

Regular monitoring of inflammatory and cardiovascular biomarkers is crucial in functional medicine to assess the effectiveness of interventions and adjust treatment plans accordingly. Here is a detailed overview of key biomarkers, their scientific evidence, and their relevance in tracking cardiovascular and inflammatory status:

Key Biomarkers

1. High-Sensitivity C-Reactive Protein (hsCRP):

• Function: hsCRP is a protein produced by the liver in response to inflammation. It is a sensitive marker of systemic inflammation and is widely used to assess cardiovascular risk.
• Evidence: Elevated hsCRP levels are associated with increased risk of cardiovascular events. The JUPITER trial demonstrated that lowering hsCRP with statin therapy reduced cardiovascular events even in patients with low LDL-C levels .
• Monitoring: Regular measurement of hsCRP helps track inflammatory status and evaluate the effectiveness of anti-inflammatory interventions.

2. Oxidized Low-Density Lipoprotein (oxLDL):

• Function: oxLDL results from the oxidative modification of LDL cholesterol. It is a key player in the development of atherosclerosis.
• Evidence: High levels of oxLDL are linked to increased risk of metabolic syndrome, coronary artery disease, and other cardiovascular conditions. Studies have shown that elevated oxLDL predicts future cardiovascular events .
• Monitoring: Measuring oxLDL provides insight into oxidative stress and the extent of atherosclerotic processes, allowing for targeted antioxidant and lifestyle interventions.

3. Asymmetric and Symmetric Dimethylarginine (ADMA/SDMA):

• Function: ADMA and SDMA are endogenous inhibitors of nitric oxide synthase, which impair nitric oxide production and contribute to endothelial dysfunction.
• Evidence: Elevated levels of ADMA are associated with cardiovascular diseases, including hypertension, atherosclerosis, and heart failure. SDMA is also considered a marker of renal function and cardiovascular risk .
• Monitoring: Tracking ADMA and SDMA levels helps assess endothelial function and the effectiveness of interventions aimed at improving nitric oxide availability.

ADMA/SDMA: Detailed Overview and Scientific Evidence

Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA) are metabolites of the amino acid L-arginine and are considered markers of endothelial dysfunction. Here’s a detailed look at their formation, function, and associated risks:

1. Formation and Function:

• L-Arginine Metabolism: L-arginine is a precursor for the synthesis of nitric oxide (NO), a critical molecule for vascular health. NO is produced by endothelial nitric oxide synthase (eNOS) and is essential for vasodilation, which helps regulate blood pressure and maintain vascular tone.
• ADMA and SDMA Formation: When L-arginine is methylated by protein arginine methyltransferases (PRMTs), it forms ADMA and SDMA. Both are released into the circulation during protein turnover.
• ADMA as an Inhibitor: ADMA directly inhibits eNOS, reducing NO production. This inhibition impairs vasodilation, leading to endothelial dysfunction.
• Indirect NO Measurement: Elevated levels of ADMA and SDMA are indirect markers of reduced NO production by the endothelium, indicating endothelial dysfunction.

2. Elevated Levels and Associated Conditions:

• Hypertension (HTN): Elevated ADMA levels are often found in individuals with hypertension. The inhibition of NO production by ADMA leads to vasoconstriction and higher blood pressure.
• Insulin Resistance: Insulin resistance is associated with increased ADMA levels, contributing to endothelial dysfunction and a higher risk of cardiovascular events.
• Hyperlipidemia: High cholesterol levels are linked to elevated ADMA, further promoting endothelial dysfunction and atherosclerosis.

3. Cardiovascular Disease (CVD) and Stroke Risk:

• CVD Risk: Elevated ADMA is associated with a 1.4x increased risk of cardiovascular disease. This association is due to ADMA’s role in inhibiting NO production, which is crucial for maintaining endothelial function and preventing atherosclerosis .
• Stroke Risk: Higher ADMA levels are linked to a 1.6x increased risk of stroke. The reduction in NO availability contributes to vascular stiffness and increased likelihood of thrombotic events, leading to stroke .
• Renal Function: Elevated SDMA levels are associated with reduced renal function. SDMA is primarily excreted by the kidneys, and its accumulation can indicate renal impairment, which is a risk factor for cardiovascular disease .

Homocysteine: Detailed Overview and Scientific Evidence

1. Formation and Function:

• Homocysteine Metabolism: Homocysteine is an intermediate amino acid formed during the metabolism of methionine. It is normally converted to cysteine or methionine in the presence of B vitamins (B6, B12, and folate).
• Endothelial Dysfunction: Elevated homocysteine levels can lead to endothelial dysfunction through increased oxidative stress, decreased NO synthesis, and changes in gene expression that affect vascular health.

2. Cardiovascular Risk:

• Mechanisms of Risk: While the exact mechanism by which homocysteine increases CAD risk is not fully understood, it likely involves oxidative stress and decreased NO activity, contributing to endothelial damage and atherogenesis.
• Goal Levels: A homocysteine level below 8 µmol/L is considered optimal. Elevated levels above 10 µmol/L significantly increase cardiovascular risk.
• Risk Association: For every 5 µmol/L increase in homocysteine above 10 µmol/L, there is an associated 1.8-fold increased risk of cardiovascular disease. Elevated homocysteine levels are linked to increased oxidative stress, impaired NO production, and endothelial dysfunction .

Scientific Evidence and Clinical Implications

1. ADMA/SDMA:

• Study Evidence: Research has shown that elevated ADMA levels are predictive of cardiovascular events and mortality. For example, a study in the Journal of the American College of Cardiology found that higher ADMA levels were associated with an increased risk of coronary artery disease and adverse cardiovascular outcomes .
• Clinical Implications: Regular monitoring of ADMA and SDMA levels can help identify individuals at higher risk for cardiovascular and renal diseases. Interventions to reduce ADMA levels, such as lifestyle modifications and medications that improve endothelial function, can potentially lower cardiovascular risk.

2. Homocysteine:

• Study Evidence: Meta-analyses and clinical studies have demonstrated that elevated homocysteine levels are associated with an increased risk of cardiovascular events. For instance, a meta-analysis in the American Journal of Clinical Nutrition highlighted the effectiveness of B-vitamin supplementation in lowering homocysteine levels and reducing cardiovascular risk .
• Clinical Implications: Monitoring homocysteine levels is important for assessing cardiovascular risk. Interventions such as dietary modifications, supplementation with B vitamins, and lifestyle changes can help lower homocysteine levels and reduce the risk of cardiovascular disease.

Regular monitoring of biomarkers like ADMA, SDMA, and homocysteine is essential for assessing endothelial function and cardiovascular risk. These biomarkers provide valuable insights into underlying physiological processes and help guide targeted interventions to improve vascular health and reduce the risk of cardiovascular events.

4. Homocysteine:

• Function: Homocysteine is an amino acid whose elevated levels are associated with endothelial damage and increased cardiovascular risk.
• Evidence: High homocysteine levels are linked to an increased risk of coronary artery disease, stroke, and peripheral arterial disease. Interventions that lower homocysteine, such as B-vitamin supplementation, have been shown to reduce cardiovascular risk .
• Monitoring: Regular measurement of homocysteine levels helps in evaluating cardiovascular risk and the impact of dietary and supplement interventions.

5. Lipid Profile:

• Components: Total cholesterol, LDL-C, HDL-C, and triglycerides.
• Evidence: Dyslipidemia, characterized by elevated LDL-C and triglycerides and low HDL-C, is a major risk factor for cardiovascular disease. Studies have consistently shown the importance of lipid management in reducing cardiovascular events .
• Monitoring: Comprehensive lipid profiling is essential for assessing cardiovascular risk and the effectiveness of lipid-lowering therapies, dietary changes, and lifestyle modifications.

Scientific Evidence and Relevance

1. hsCRP:

• Study: The JUPITER trial showed that participants with low LDL-C but high hsCRP who were treated with rosuvastatin had a significant reduction in cardiovascular events compared to those on placebo .
• Clinical Implication:
  

  hsCRP is a valuable marker for identifying individuals at high cardiovascular risk who may benefit from anti-inflammatory treatment even if their LDL-C levels are not elevated.

2. oxLDL:

• Study: A study published in “Arteriosclerosis, Thrombosis, and Vascular Biology” found that elevated oxLDL levels were predictive of future cardiovascular events and were associated with metabolic syndrome .

• Clinical Implication: Measuring oxLDL helps identify patients with increased oxidative stress and atherogenic risk, guiding the use of antioxidants and lifestyle interventions.

3. ADMA/SDMA:

• Study: Research published in the “Journal of the American College of Cardiology” highlighted that elevated ADMA levels are predictive of cardiovascular events and mortality in patients with coronary artery disease .

• Clinical Implication: Monitoring ADMA and SDMA levels can help evaluate endothelial function and guide interventions to enhance nitric oxide availability and vascular health.

4. Homocysteine:

• Study: A meta-analysis in “The American Journal of Clinical Nutrition” demonstrated that B-vitamin supplementation effectively lowers homocysteine levels and reduces cardiovascular risk in high-risk populations .
• Clinical Implication: Regular homocysteine monitoring helps tailor dietary and supplement interventions to reduce cardiovascular risk.

5. Lipid Profile:

• Study: The Framingham Heart Study and numerous clinical trials have established the relationship between lipid levels and cardiovascular risk, supporting the importance of lipid management .
• Clinical Implication: Comprehensive lipid profiling is crucial for evaluating cardiovascular risk and the success of interventions aimed at improving lipid levels.

Functional Medicine Approach

1. Personalized Assessment:

• Functional medicine practitioners conduct comprehensive evaluations, including detailed medical history, lifestyle factors, and biomarker testing, to identify the underlying causes of chronic inflammation and cardiovascular risk.

2. Targeted Interventions:

• Based on biomarker results, personalized treatment plans are developed, which may include dietary modifications, supplements, lifestyle changes, and specific therapies to address inflammation, oxidative stress, and lipid imbalances.

3. Continuous Monitoring and Adjustment:

• Regular monitoring of biomarkers allows for the assessment of treatment effectiveness and timely adjustments to interventions, ensuring optimal patient outcomes.

4. Holistic Approach:

• Functional medicine emphasizes a holistic approach, considering the interconnectedness of body systems and the impact of lifestyle, nutrition, and environmental factors on health.

Regular monitoring of inflammatory and cardiovascular biomarkers is essential in functional medicine to effectively manage chronic inflammation and reduce cardiovascular risk. By tracking markers like hsCRP, oxLDL, ADMA/SDMA, homocysteine, and lipid profiles, practitioners can tailor interventions to each individual’s unique needs, promoting better health outcomes and preventing cardiovascular disease.

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References:

1. Ridker PM, et al. “Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.” New England Journal of Medicine. 2008.
2. Holvoet P, et al. “Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome.” JAMA. 2008.
3. Tsimikas S, et al. “Oxidized low-density lipoprotein biomarkers in coronary artery disease.” Journal of the American College of Cardiology. 2003.
4. Böger RH, et al. “Asymmetric dimethylarginine (ADMA): a novel risk marker in cardiovascular medicine and beyond.” Annals of Medicine. 2006.
5. Lüneburg N, et al. “Symmetric dimethylarginine is a marker of detrimental outcome in the acute phase after ischemic stroke: role of renal function.” Clinical Chemistry and Laboratory Medicine. 2012.
6. Homocysteine Studies Collaboration. “Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.” JAMA. 2002.
7. Wald DS, et al. “Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.” BMJ. 2002.
8. Castelli WP. “The Triglyceride Issue: A View from Framingham.” American Heart Journal. 1986.
9. Gordon DJ, et al. “High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.” Circulation. 1989.

Monitoring Markers

Endothelial Dysfunction:

• ADMA/SDMA (Asymmetric and Symmetric Dimethylarginine): Inhibit nitric oxide synthesis, indicating endothelial dysfunction.
• Homocysteine: Elevated levels can damage endothelial cells.
• Microalbumin: Indicates early kidney damage and endothelial dysfunction.
• Blood Pressure (BP): Chronic hypertension is a marker and contributor to endothelial dysfunction.
• Insulin Resistance (IR) Markers: High fasting insulin or HOMA-IR scores.
• Cholesterol: LDL-C, HDL-C, triglycerides.
• Inflammatory Markers: CRP, IL-6.
• TMAO: Elevated levels linked to cardiovascular risk.

Inflammation:

• hsCRP (High-Sensitivity C-Reactive Protein): A marker of systemic inflammation.
• oxLDL: Indicates oxidative modification of LDL.
• LpPLA2 (Lipoprotein-associated Phospholipase A2): Marker of vascular inflammation.
• Smoking: Known risk factor for chronic inflammation.
• Dietary Factors: Gluten and sugar intake can influence inflammation levels.

Cholesterol:

• Lipid Profile: Includes total cholesterol, LDL-C, HDL-C, and triglycerides.
• LDL-P: Number of LDL particles.
• Lp(a) (Lipoprotein(a)): Genetic risk factor for cardiovascular disease.
• ApoB (Apolipoprotein B): Represents the number of atherogenic particles.
• ApoA1 (Apolipoprotein A1): Major protein component of HDL, inversely related to cardiovascular risk.

High-Sensitivity C-Reactive Protein (hsCRP)

1. Overview:

• hsCRP is an acute-phase reactant protein produced by the liver in response to inflammation. It is a sensitive marker of systemic inflammation and can be elevated in various conditions such as exercise, acute illness, and chronic inflammatory diseases like periodontal disease.

2. Cardiovascular Risk:

• Elevated hsCRP levels are associated with a 4x increased risk of cardiovascular disease (CVD).
• The JUPITER trial demonstrated that treatment with statins, which reduce hsCRP levels, also reduced cardiovascular events even in patients with low LDL-C levels but high hsCRP.
• Individuals with low LDL-C but high hsCRP have double the risk of CVD compared to those with low LDL-C and low hsCRP, highlighting the importance of considering multiple markers for a comprehensive risk assessment.
• Lowering hsCRP has been shown to result in a 15% relative risk reduction in CVD events.

Oxidized Low-Density Lipoprotein (oxLDL)

1. Mechanism:

• oxLDL measures the damage due to oxidative modification of the ApoB subunit on LDL cholesterol.
• LDL particles undergo oxidation within the arterial wall, marking one of the initial steps in the development of atherosclerosis.
• Oxidized LDL is then taken up by macrophages, leading to the formation of foam cells and promoting vascular inflammation.

2. Health Implications:

• Patients with high levels of oxLDL are 3.5 times more likely to develop metabolic syndrome within the next five years.
• Healthy middle-aged men with high oxLDL levels have a 4x increased risk of developing coronary artery disease (CAD).
• Elevated oxLDL levels can also be found in individuals with autoimmune diseases, chronic kidney disease (CKD), and polycystic ovary syndrome (PCOS).

Importance of Multi-Marker Strategies

• The data from studies like the JUPITER trial underscore the importance of using multi-marker strategies to assess cardiovascular risk comprehensively. Solely focusing on LDL-C may overlook significant risk factors that are evident with markers like hsCRP and oxLDL.
• Using a combination of markers, including hsCRP, oxLDL, LDL-P, ApoB, and others, provides a more accurate and detailed picture of an individual’s cardiovascular health and inflammation status.

Monitoring Markers

1. Endothelial Dysfunction:

• ADMA/SDMA: Indicators of nitric oxide synthesis inhibition.
• Homocysteine: Elevated levels can indicate endothelial damage.
• Microalbumin: Marker for early kidney and endothelial dysfunction.
• Blood Pressure (BP): Elevated BP can indicate endothelial stress.
• Insulin Resistance (IR) Markers: High fasting insulin or HOMA-IR scores.
• Cholesterol Levels: LDL-C, HDL-C, triglycerides.
• Inflammatory Markers: CRP, IL-6.
• TMAO: Elevated levels linked to cardiovascular risk.

2. Inflammation:

• hsCRP: High levels indicate systemic inflammation and increased CVD risk.
• oxLDL: Measures oxidative damage and predicts future risk of metabolic syndrome and CAD.
• LpPLA2: Indicates vascular inflammation.
• Smoking: Increases inflammation.
• Dietary Factors: High intake of gluten and sugar can raise inflammation levels.

3. Cholesterol:

• Lipid Profile: Includes total cholesterol, LDL-C, HDL-C, and triglycerides.
• LDL-P: Number of LDL particles.
• Lp(a): Genetic risk factor for cardiovascular disease.
• ApoB: Represents the number of atherogenic particles.
• ApoA1: Major protein component of HDL, inversely related to cardiovascular risk.

Understanding the mechanisms behind chronic inflammation and endothelial dysfunction, along with their monitoring, is crucial for managing and reducing cardiovascular risk. By using a comprehensive approach that includes multiple biomarkers, healthcare providers can better identify and treat individuals at high risk, thereby improving cardiovascular outcomes.

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